title: Discovering isozyme-selective inhibitor scaffolds of human carbonic anhydrases using structural alignment and de novo drug design approaches.
abstract: The development of isozyme-selective carbonic anhydrase inhibitors is currently still a great challenge. In the present study, protein-ligand complex structures were obtained by AutoDock Vina with SBR ((R)-N-(3-indol-1-yl-2-methyl-propyl)-4-sulfamoyl-benzamide) as the only inhibitor docked into the binding pockets of human isozymes CA I, II, IV, VI, IX, XII, and XIII. To make the spatial structures of complexes comparable, the co-ordinates for CA domains were reassigned based on structural alignments. With preferred docking poses of SBR been reduced to seed structures, the LigBuilder was used to build up inhibitor molecules. The results suggested that sulfonamide derivatives with naphthalene, fluorene, and acridan as the scaffold structures can be the potential isozyme-selective CAIs, especially for isozymes CA II, IV, and IX.
authors.affiliation: Hubei Key Laboratory of Economic Forest Germplasm Improvement and Resources Comprehensive Utilization, Huanggang Normal University, Huanggang, 438000, China.
authors.forename: Fu
authors.initials: F
authors.lastname: Xiang
authors.forename: Jun
authors.initials: J
authors.lastname: Xiang
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Fang
authors.forename: Mingju
authors.initials: M
authors.lastname: Zhang
authors.forename: Maoteng
authors.initials: M
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D020134:Catalytic Domain; D030562:Databases, Protein; D015195:Drug Design; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D016415:Sequence Alignment; D012984:Software
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D002256:Carbonic Anhydrases
keywords: carbonic anhydrase; drug design; molecular docking; selective inhibitor; structural alignment